Ultragenyx Pharmaceutical Inc. announced that all patients have been enrolled across the Phase 3 Orbit and Cosmic studies evaluating setrusumab (UX143) in pediatric and young adult patients with osteogenesis imperfecta (OI). The pivotal Phase 3 portion of the Orbit study has randomized 158 patients ages 5 to 25 years, and the Cosmic study has completed enrollment of 66 patients ages 2 to <7 years. Data presented at the American Society for Bone and Mineral Research 2023 Annual Meeting (ASBMR) from the Phase 2 portion of the Orbit study showed that treatment with setrusumab reduced the median annualized fracture rate by 67% and this reduction was associated with continuing large and meaningful improvements in bone mineral density (BMD).

Setrusumab was generally well tolerated with no drug-related serious adverse events (SAEs) reported and no reports of drug-related hypersensitivity. Additional longer-term Phase 2 safety and efficacy data from the Orbit study are expected in the second half of 2024. Ultragenyx is developing setrusumab in pediatric and young adult patients across OI sub-types I, III and IV with two late-stage trials: the pivotal Phase 2/3 Orbit study and Phase 3 Cosmic study.

The global, seamless Phase 2/3 Orbit study is evaluating the effect of setrusumab on clinical fracture rate in patients aged 5 to 25 years. In the Phase 2 portion, 24 patients were randomized 1:1 to receive setrusumab at one of two doses to determine the optimal dosing strategy for Phase 3. The pivotal Phase 3 portion of the study has enrolled an additional 158 patients at 45 sites across 11 countries, with subjects randomized 2:1 to receive setrusumab or placebo, and a primary efficacy endpoint of annualized clinical fracture rate. All patients will transition to an extension period and receive open-label setrusumab after the Phase 3 primary analysis is complete.

The global Phase 3 Cosmic study is an open-label, randomized, active-controlled study in patients aged 2 to <7 years. Patients are randomized 1:1 to receive setrusumab or intravenous bisphosphonates (IV-BP) therapy to evaluate reduction in total fracture rate. The Cosmic study has enrolled 66 patients at 21 sites across 7 countries.

There are up to two planned interim analyses for the Orbit study, and the first is anticipated by year-end or early 2025 based on the timing of enrollment. The first analysis will have a stringent threshold of p = 0.001. If the threshold is not met, a second interim analysis will occur a few months after, followed by a final analysis at 18 months.

Interim analyses will not be reported to the company by the data monitoring committee unless they are positive. In the event of a positive interim analysis, the patients will complete a final visit prior to transitioning to the open-label extension study and reporting of topline results. About Osteogenesis Imperfecta (OI): Osteogenesis Imperfecta (OI) includes a group of genetic disorders impacting bone metabolism.

Approximately 85% to 90% of OI cases are caused by genetic variants in the COL1A1 or COL1A2 genes, leading to either reduced or abnormal collagen and changes in bone metabolism. The collagen mutations in OI can result in increased bone brittleness, which contributes to a high rate of fractures. Patients with OI also exhibit inadequate production of new bone and excess bone resorption, resulting in decreased bone mineral density, bone fragility and weakness.

OI can also lead to bone deformities, abnormal spine curvature, pain, decreased mobility, and short stature. No treatments are globally approved for OI, which affects approximately 60,000 people in commercially accessible geographies. About Setrusumab (UX143): Setrusumab is a fully human monoclonal antibody that inhibits sclerostin, a negative regulator of bone formation.

Blocking sclerostin is expected to increase new bone formation, bone mineral density and bone strength in OI. In mouse models of OI, the use of anti-sclerostin antibodies was shown to increase bone formation, improve bone mass to normal levels, and increase bone strength against fracture force testing to normal levels. In 2019 Mereo BioPharma completed the Phase 2b dose-finding study (ASTEROID) for setrusumab in 112 adults with OI.

The ASTEROID study demonstrated treatment with setrusumab resulted in a clear, dose-dependent and statistically significant effect on bone formation and bone density at multiple anatomical sites among adult participants with OI. Ultragenyx and Mereo BioPharma are collaborating on the development of setrusumab globally based on the collaboration and license agreement between the parties. The companies have developed a comprehensive late-stage program to continue development of setrusumab in pediatric and young adult patients across OI sub-types I, III and IV.